Restenosis is a significant impediment to treatments for atherosclerosis including bypass surgery, endarterectomy, and angioplasty and stenting, and occurs in up to 30- 50% of patients following angioplasty and stenting. Understanding the molecular mechanisms that drive neointimal hyperplasia and arterial remodeling, two main contributors to restenosis, will ultimately allow for the development of therapies that prevent or halt the progression of this serious process. Restenosis is in part caused by a complex process called intimal hyperplasia. The neointimal lesion is comprised of proliferating smooth muscle cells (SMCs) and extracellular matrix. New evidence suggests that bone marrow-derived progenitor cells (BMPCs) recruited to sites of vascular injury also contribute to the neointima. BMPCs are considered multipotent in that they are capable of differentiating into numerous cell types including fibroblasts and SMCs. However, the mechanisms through which progenitor cells are recruited into the injured artery have not been described. Transforming Growth Factor-Beta (TGF-Beta), upregulated at the site of vascular injury, plays a critical role in the genesis of restenosis following vascular intervention. Our previous studies revealed that TGF-Beta's contribution to intimal hyperplasia is primarily related to cell proliferation and matrix remodeling. Moreover, TGF-Beta through its actions on SMCs may also significantly enhance progenitor cell recruitment. TGF-Beta's effect may be mediated by its signaling protein, Smad3, and lead to the production of chemokines by SMCs. Our gene array studies have demonstrated that in TGF-Beta-stimulated Smad3-expressing SMCs, Monocyte Chemotactic Protein-1 (MCP-1) is expressed over 80-fold. Our hypothesis is that TGF-Beta, through Smad3 signaling, stimulates SMCs to produce chemokines such as MCP-1, which attract bone marrow cells to the site of arterial injury thereby enhancing the development of intimal hyperplasia. PUBLIC HEALTH RELEVANCE: Restenosis is a significant impediment to treatments for atherosclerosis and occurs in up to 30-50% of patients following vascular interventions. Bone marrow-derived progenitor cells have been found to contribute to neointimal hyperplasia, one of the two main contributors to restenosis. However, the mechanisms through which progenitor cells are recruited have not been described. Our hypothesis is that TGF-Beta, through Smad3 signaling, stimulates smooth muscle cells in the vascular wall to produce factors such as monocyte chemoattractant protein-1 to attract bone marrow cells to sites of arterial injury.